Various 1,5,10,11-tetrahydrobenzo [4,5]-cyclohepta [1,2-b]pyrazolo[4,3-e]pyridine derivatives

ABSTRACT

Compounds of the formulas  wherein R 1  is lower alkyl, phenyl, benzyl or phenethyl; R 2  is hydrogen, lower alkyl or phenyl; R is ##STR1## N IS AN INTEGER FROM 3 TO 6; R 3  and R 4  are each lower alkyl or R 3  and R 4  taken together with the N-atom form a heterocyclic ring of the formula ##STR2## wherein R 5  is hydrogen, lower alkyl, or lower alkoxy; and pharmaceutically acceptable acid addition salts thereof are disclosed. These compounds and their salts possess central nervous system activity and are useful as anti-anxiety agents.

SUMMARY OF THE INVENTION

This invention relates to new1,5,10,11-tetrahydrobenzo[4.5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridinesand their acid addition salts of the formulas ##STR3## R₁ is loweralkyl, phenyl, benzyl, or phenethyl. R₂ is hydrogen, lower alkyl, orphenyl.

R is ##STR4## N IS AN INTEGER FROM 3 TO 6. R₃ and R₄ are the same ordifferent and each is lower alkyl or R₃ and R₄ taken together with theN-atom form a heterocyclic of the formula ##STR5## wherein R₅ ishydrogen, lower alkyl or lower alkoxy.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used throughout this specification is meant toinclude straight or branched chain hydrocarbon groups having from 1 to 4carbon atoms, i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,and t-butyl. Similarly, the term "lower alkoxy" is meant to include suchalkyl groups linked to an oxygen atom, i.e. methoxy, ethoxy, t-butoxy,etc.

Preferred embodiments of this invention are the compounds of formulas Iand II wherein:

R₁ is lower alkyl of 1 to 4 carbons, especially ethyl.

R₂ is hydrogen.

R is ##STR6## n is 3. R₃ and R₄ are the same and are methyl or ethyl,especially methyl.

The new compounds of formula I can be prepared by several methods. Thepreferred methods involve reacting a ketone of the formula ##STR7## witha Grignard reagent of the formula ##STR8## wherein Hal is Cl or Br andn, R₁ R₂, R₃ and R₄ are as defined above. This reaction is carried outin an inert solvent such as diethylether, dibutylether, ortetrahydrofuran by heating at about the reflux temperature for severalhours.

Alternatively, certain compounds of formula I wherein n is three canalso be prepared by reacting the ketone of formula II with an alkylmagnesium halide Grignard reactant of the formula

    Hal--Mg--CH.sub.2 --CH=CH.sub.2                            (VI)

to yield the compound of the formula ##STR9## Amination of the olefiniclinkage of the compound of formula VII by reacting with an amine##STR10## yields the compound of formula I wherein n is 3.

Also, the ketone of formula III can be reacted with a dialkylaminoalkyneof the formula ##STR11## in the presence of a condensing agent such assodium or lithium amide to yield the compound of the formula ##STR12##Hydrogenation of the compound of formula IX yields the correspondingcompound of formula I.

The new compounds of formula II are prepared by dehydrating the compoundof formula I wherein R is ##STR13## The dehydration is accomplished byheating the compound of formula I in an acid such as hydrochloric acid,polyphosphoric acid, etc., or a dehydrating agent such as aceticanhydride. The compounds of formula II are obtained as a mixture of thecis and trans isomers.

The preparation of the starting materials of formula III are disclosedin U.S. Ser. No. 670,332 filed on Mar. 25, 1976. As disclosed therein a5-aminopyrazole of the formula ##STR14## [prepared according to theprocedure described in Z. f. Chemie 10, 386-388 (1970)] is reacted witha phenylpropionyl malonic acid dialkylester of the formula ##STR15##[prepared according to the procedure described in J. Chromatography 47,479 (1970)] by heating at a temperature of about 120° C. in the presenceof polyphosphoric acid, producing a compound of the formula ##STR16##

The intermediate of formula XII is saponified by means of a basic agentlike sodium hydroxide, etc., to yield an acid of the formula ##STR17##

The compound of formula XIII is then cyclized by heating at atemperature of about 120° using polyphosphoric acid as the ring closureagent, to produce a compound of the formula ##STR18##

The tetracyclic heterocycle of the formula XIV is treated with aninorganic acid chloride or bromide such as phosphorous oxychloride,thionyl chloride, etc., to yield a compound of the formula ##STR19##wherein X is Cl or Br.

Treatment of the compound of the formula XV with triethylamine andhydrogenation with palladium on charcoal yields the starting material offormula III.

Depending on the reaction conditions and the starting materials used,the compounds of formulas I and II are obtained in the free form or inthe form of their acid addition salts. The salts thereof can beconverted into the free compounds in a known manner such as by reactionwith a basic agent. Free bases which may be obtained can be convertedinto pharmaceutically acceptable acid addition salts by reaction with avariety of acids. Acids useful for preparing these acid-addition saltsinclude, inter alia, inorganic acids, such as the hydrohalic acids (e.g.hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, andphosphoric acid, and organic acids such as maleic, fumaric, tartaric,citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic,nicotinic, methanesulfonic or cyclohexanesulfamic.

The new compounds of formulas I and II including their acid additionsalts are capable of modifying the central nervous system. Whenadministered to mice, cats, rats, dogs, and other mammalian species inamounts ranging from about 0.5 mg. to about 100 mg. per kg. of bodyweight per day, these compounds in particular exhibit anti-anxietyactivity. A preferred dosage regimen for optimum results would be fromabout 1 mg. to about 5 mg. per kg. of body weight per day, and suchdosage units are employed so that a total of from about 35 mg. to about3 g. of active ingredient in single or divided doses are administered ina 24 hour period.

Compounds of formula I when administered to rats within the above statedpreferred dosage range produced a significant anti-anxiety effect asdemonstrated by increases in behavior which were formerly suppressed bypunishment in a conflict test procedure [cf. J. R. Vogel, B. Beer, D.Clody, Psychopharmacologist, 21, 1 (1970)].

For this pharmaceutical purpose a compound or mixture of compounds offormulas I and II or their pharmaceutically acceptable acid additionsalts may be administered orally or parenterally in a conventionaldosage form such as tablet, capsule, injectable or the like. These maybe conventionally formulated in an oral or parenteral dosage form bycompounding with a conventional vehicle, excipient, binder,preservative, stabilizer, flavor or the like as called for by acceptedpharmaceutical practice.

The following examples are illustrative of the invention and representpreferred embodiments. Other modifications may be readily produced bysuitable variations of the reactions. All temperatures are on thecentigrade scale.

EXAMPLE 15-[3-(Dimethylamino)propyl]-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol,hydrochloride (1:2)

(a)1-Ethyl-4-hydroxy-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, ethyl ester

43.6 g. of (3-phenylpropionyl)malonic acid, diethyl ester (0.15 mol.)are added to a stirred mixture of 16.5 g. of 5-amino-1-ethylpyrazole(0.15 mol.) and 220 g. of polyphosphoric acid. The mixture is heated to120° (bath temperature) for 50 minutes. After the mixture has cooled toroom temperature, 250 ml. of water are added in portions and stirring iscontinued for 20 minutes. The aqueous phosphoric acid solution is thendecanted and the undissolved residue is treated with 200 ml. of waterand aqueous ammonia (10%) to neutralize the mixture. The mixture isextracted with chloroform and the chloroform extract is washed twicewith water, dried with Na₂ SO₄ and evaporated to yield 39 g. of the oilyproduct. Dissolution of the oil in about 250 ml. of ether and additionof ethereal hydrogen chloride yields 35 g. (62%) of1-ethyl-4-hydroxy-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, ethyl ester, hydrochloride, m.p. 153°-155° (ethanol/ethyl acetate1:1).

(b)1-Ethyl-4-hydroxy-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid

64 g. of1-ethyl-4-hydroxy-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, ethyl ester, hydrochloride (0.17 mol.), dissolved in 800 ml. ofaqueous sodium hydroxide (20%), are heated at 80°-85° (bath temperature)for 44 hours. The solution is treated with charcoal, filtered and thenacidified with half-concentrated hydrochloric acid. The precipitated1-ethyl-4-hydroxy-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid is filtered off, washed with water and dried in a desiccator togive 46.5 g. (88%) of1-ethyl-4-hydroxy-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid, m.p. 160°-161° (absolute ethanol).

(c)1-Ethyl-10,11-dihydro-4-hydroxybenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)one

46.6 g. of1-ethyl-4-hydroxy-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylicacid (0.15 mol.) and 300 g. of polyphosphoric acid are heated at200°-220° (bath temperature) with stirring for 20 minutes. After themixture has cooled to room temperature, 700 ml. of ice-water are addedslowly with stirring. The stirring is continued until the compoundbecomes crystalline. The collected ketone is then dissolved inchloroform and the solution is washed with water, treated with charcoaland dried (Na₂ SO₄). Evaporation of the solution yields 30.3 g. (69%) of1-ethyl-10,11-dihydro-4-hydroxybenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)one,m.p. 154°-155° (hexane).

(d)4-Chloro-1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)one

26.5 g. of1-ethyl-10,11-dihydro-4-hydroxybenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)one(0.09 mol.) are refluxed in 350 ml. of phosphorous oxychloride for 5hours. The excess phosphorous oxychloride is removed in vacuo and theresidue is treated with water and extracted with ether. The etherealsolution is washed twice with water, dried (Na₂ SO₄) and then evaporatedto give 26 g. (93%) of4-chloro-1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)one,m.p. 111°-113° (hexane/cyclohexane 2:1).

(e)1-Ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)one

To a solution of 23.3 g. of4-chloro-1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)one(0.075 mol.) in 450 ml. absolute ethanol are added 22.5 g. oftriethylamine and 2 g. of palladium on charcoal (10%). The mixture ishydrogenated at room temperature. After the solution has absorbed thetheoretical amount of hydrogen, the reaction is filtered and the alcoholis removed by distillation. The residue is treated with water and afterstirring for 20 minutes the compound is extracted with ether. Theethereal solution is washed with water, dried with anhydrous sodiumsulfate and evaporated yielding 18.2 g. (88%) of1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)one,m.p. 88°-90° (hexane).

(f)5-[3-(Dimethylamino)propyl]-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol,hydrochloride (1:2)

40 g. (0.33 mol.) of freshly distilled and absolutely dry3-dimethylaminopropyl chloride are added slowly with stirring and gentleheating to 8.0 g. of magnesium turnings in 200 ml. of drytetrahydrofuran. A crystal of iodine and a few drops of ethyl iodide areemployed as initiator. After all of the 3-dimethylaminopropyl chlorideis added, the reaction mixture is refluxed for two to three hours. ThisGrignard reagent is then added to a solution of 30.5 g. (0.11 mol.) of1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-onein 200 ml. of dry tetrahydrofuran. The mixture is heated under refluxfor two hours afterwhich the solvent is evaporated and the residuedecomposed with 100 ml. of ice-water and 180 ml. of ammonium chloridesolution (20%). This mixture is extracted with ether and the etherealextract is washed with water, dried with Na₂ SO₄, and the solventevaporated to yield 28.7 g. (72%) of oily5-[3-(dimethylamino)propyl]-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol.

This oil is dissolved in 250 ml. of dry ether and 22 ml. of etherealhydrochloric acid (256 g. HCl/l.) are added to yield 25 g. of crudehydrochloride salt; m.p. 100°-102°. A sample of this salt isrecrystallized from ethyl acetate/ether (1:2) to yield5-[3-(dimethylamino)propyl]-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol,hydrochloride (1:2); m.p. 101°-103° (dec.).

EXAMPLES 2-20

Following the procedure of example 1 but employing the substituted5-aminopyrazole shown below in Col. I one obtains the10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-oneshown in Col. II. Reaction of the ketone of Col. II with the Grignardreactant shown in Col. III yields the final product shown in Col. IV.

    __________________________________________________________________________    Col. I               Col. II                                                   ##STR20##                                                                                          ##STR21##                                               Col. III             Col. IV                                                   ##STR22##                                                                                          ##STR23##                                                Ex.                                                                               R.sub.1    R.sub.2                                                                              n                                                                                  ##STR24##                                         __________________________________________________________________________    2  CH.sub.3   H      3                                                                                    ##STR25##                                         i-C.sub.3 H.sub.7                                                                H          4                                                                                     ##STR26##                                               4                                                                             n-C.sub.4 H.sub.9                                                                H          3                                                                                     ##STR27##                                               5                                                                             t-C.sub.4 H.sub.9                                                                CH.sub.3   3                                                                                     ##STR28##                                               6  H          H      5                                                                                    ##STR29##                                         7                                                                                 ##STR30## C.sub.2 H.sub.5                                                                      3                                                                                    ##STR31##                                         8                                                                                 ##STR32## H      6                                                                                    ##STR33##                                         9                                                                                 ##STR34## H      3                                                                                    ##STR35##                                         10 C.sub.2 H.sub.5                                                                          CH.sub.3                                                                             3                                                                                    ##STR36##                                         11 C.sub.2 H.sub.5                                                            t-C.sub.4 H.sub.9                                                                3                                                                                         ##STR37##                                                      12 C.sub.2 H.sub.5                                                                           ##STR38##                                                                           4                                                                                    ##STR39##                                         13 C.sub.2 H.sub.5                                                                          H      3                                                                                    ##STR40##                                         14 CH.sub.3   C.sub.2 H.sub.5                                                                      4                                                                                    ##STR41##                                         15 C.sub.2 H.sub.5                                                                          H      6                                                                                    ##STR42##                                         16 C.sub.2 H.sub.5                                                                          H      3                                                                                    ##STR43##                                         17 C.sub.2 H.sub.5                                                                          H      3                                                                                    ##STR44##                                         18                                                                                ##STR45## H      4                                                                                    ##STR46##                                         19 C.sub.2 H.sub.5                                                                           ##STR47##                                                                           3                                                                                    ##STR48##                                         20 C.sub.2 H.sub.5                                                                          CH.sub.3                                                                             5                                                                                    ##STR49##                                         __________________________________________________________________________

example 211-ethyl-1,5,10,11-tetrahydro-5-(1-methyl-4-piperidinyl)benzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol,hydrochloride (1:2)

13.4 g. (0.1 mol.) of freshly distilled and absolutely dry4-chloro-1-methylpiperidine and a few drops of ethyl iodide are added to2.4 g. (0.1 mol.) of magnesium turnings. After all of the4-chloro-1-methylpiperidine is added, the mixture is refluxed for threehours with stirring. After cooling, this Grignard reagent is added to asolution of 9.7 g. (0.035 mol.) of1-ethyl-10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-onefrom example 1(e) in 75 ml. of dry tetrahydrofuran. While stirring, themixture is refluxed for three hours. The solvent is then distilled offand the residue is treated successively with 50 ml. of ice-water and 100ml. of a 20% aqueous ammonium chloride solution. This mixture isextracted with ether and the ethereal extract is washed with water,dried with Na₂ SO₄, and the solvent is evaporated to yield 6.5 g.(49.5%) of1-ethyl-1,5,10,11-tetrahydro-5-(1-methyl-4-piperidinyl)benzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol;m.p. 189°-191° (cyclohexane).

This material is dissolved in ethyl acetate and ethereal hydrochloricacid is added to yield1-ethyl-1,5,10,11-tetrahydro-5-(1-methyl-4-piperidinyl)benzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol,hydrochloride (1:2); m.p. 190°-191° (dec.).

EXAMPLES 22-27

Following the procedure of example 21 but employing the Grignardreactant shown below in Col. I one obtains the final products shownbelow in Col. II.

    __________________________________________________________________________    Col. I       Col. II                                                           ##STR50##                                                                                  ##STR51##                                                       Ex.          alkyl                                                            __________________________________________________________________________    22           C.sub.2 H.sub.5                                                  23                                                                            n-C.sub.3 H.sub.7                                                             24                                                                            i-C.sub.3 H.sub.7                                                             25                                                                            n-C.sub.4 H.sub.9                                                             26                                                                            i-C.sub.4 H.sub.9                                                             27                                                                            t-C.sub.4 H.sub.9                                                             __________________________________________________________________________

similarly, by employing the10,11-dihydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-onesshown in Col. II of examples 2 to 20 within the procedure of examples21-27, other compounds within the scope of the invention are obtained.

EXAMPLE 285-[3-(Dimethylamino)propylidene]-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine,hydrochloride (1:2)

14.5 g. (0.033 mol.) of5-[3-(dimethylamino)propyl]-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine-5-ol,hydrochloride (1:2) from example 1(f) are suspended in 125 ml. of aceticanhydride. After the addition of a few drops of pyridine, the mixture isheated at 55°-60° (bath temperature) for 14 hours with stirring. Theresulting solution is filtered, evaporated, and the residual oilycompound is extracted into ether. The ethereal extract is washed with anaqueous sodium bicarbonate solution and water (twice) and dried withanhydrous sodium sulfate. Removal of the ether leaves 11 g. of oily5-[3-(dimethylamino)propylidene]-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine.

This oil is dissolved in 75 ml. of anhydrous ether and treated withethereal hydrochloric acid while stirring to yield a crude hydrochloridesalt. Recrystallization from a mixture of ethyl acetate and ether yields5.2 g. (38%) of hygroscopic5-[3-(dimethylamino)propylidene[-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine,hydrochloride (1:2); m.p. 79°-81°.

Similarly, by employing the dehydration procedure of example 28 on theproducts shown in Col. IV of examples 2 to 20, other compounds withinthe scope of the invention are obtained.

What is claimed is:
 1. A compound of the formula: ##STR52## wherein R₁is lower alkyl of 1 to 4 carbons, phenyl, benzyl or phenethyl; R₂ ishydrogen, lower alkyl of 1 to 4 carbons, or phenyl; R is ##STR53##wherein alkyl is straight or branched chain of 1 to 4 carbons and R₃ andR₄ are the same or different and each is lower alkyl of 1 to 4 carbonsor R₃ and R₄ taken together with the N-atom form a heterocyclic ringselected from the group consisting of ##STR54## wherein R₅ is hydrogen,lower alkyl of 1 to 4 carbons, or lower alkoxy of 1 to 4 carbons; n isan integer from 3 to 6; and a pharmaceutically acceptable acid additionsalt thereof.
 2. The compound of claim 1 wherein R is ##STR55## andalkyl is straight or branched chain of 1 to 4 carbons.
 3. The compoundof claim 2 wherein R₁ is lower alkyl of 1 to 4 carbons and R₂ ishydrogen.
 4. The compound of claim 3 wherein R is ##STR56## and R₁ isethyl.
 5. The compound of claim 4,1-ethyl-1,5,10,11-tetrahydro-5-(1-methyl-4-piperidinyl)benzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol,hydrochloride (1:2).
 6. The compound of claim 1 wherein R is ##STR57##and n is an integer from 3 to 6 and R₃ and R₄ are the same or differentand each is lower alkyl of 1 to 4 carbons.
 7. The compound of claim 6wherein R₁ is lower alkyl of 1 to 4 carbons, R₂ is hydrogen, n is 3 or4, and R₃ and R₄ are the same and each is methyl or ethyl.
 8. Thecompound of claim 7 wherein R₁ is ethyl, n is 3, and R₃ and R₄ are eachmethyl.
 9. The compound of claim 8,5-[3-(dimethylamino)propyl]-1-ethyl-1,5,10,11-tetrahydrobenzo[4,5]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-5-ol,hydrochloride (1:2).
 10. The compound of claim 1 wherein R is ##STR58##and n is an integer from 3 to 6 and R₅ is hydrogen, lower alkyl of 1 to4 carbons, or lower alkoxy of 1 to 4 carbons.
 11. The compound of claim10 wherein R₁ is lower alkyl of 1 to 4 carbons, R₂ is hydrogen, n is 3or 4, and R₅ is hydrogen, methyl, or methoxy.
 12. The compound of claim11 wherein R₁ is ethyl and n is 3.